There are two overall themes interrelating the four projects. First, the Bevan and Klinman laboratories (projects I and II) will address the developmental basis of T and B cell receptor repertoire expression. Since the repertoire of mature T cell receptors is determined largely by thymic environmental selection, the Bevan laboratory will assess the impact on their fine specificity of T cells developing in the presence of wild type vs mutant MHC molecules. The clonal development of neonatal and adult B cell subsets will be addressed at the molecular level by the Klinman laboratory which will use PCR technology to generate libraries of V region sequences from the genomic DNA of developing B lineage cell clones. The Bevan laboratory, in addressing the tripartite interaction of T cell receptors, peptides, and MHC molecules, and the Klinman laboratory in assessing B cell repertoire diversity, will both participate in the second overall theme, the structure of receptor-antigen interaction and its relationship to repertoire diversity. The Getzoff laboratory will continue its promising analyses of the structure of an Fab fragment of anti cytochrome c antibody and the same Fab in complex with antigen. These studies should provide crucial information concerning the contacts made between antibodies and antigens and the flexibility of interacting molecules. This information serves as the backdrop for the Lerner laboratory, which proposes to continue its pioneering efforts to predict and find antibody combining site structures capable of catalyzing chemical reactions. During the past several years the principle investigators have profited greatly from the common CORE facility made available through this program project and the intellectual interactions the grant has fostered. The present proposal is intended to facilitate the continuation of these interactions.